Beta-(2-biphenyloxy) ethyl beta-haloalkyl amines



Patented Jan. 31, 1950 UNITED STATES PATENT OFFICE BETA-(z-nrrnnmoxxm'rm BETA- HALOALKYL AMINES George Rieveschl, Jr., andRobert W. Fleming, Grosse Pointe Woods, Mich., asslgnors to Parke, Davis& Company, Detroit, Mich., a corporation of Michigan No Drawing.Application February 7, 1947,

. Serial No. 727,287

6 Claims. (Cl. 260-5701) where R is a lower alkyl or alkenyl radical, R1is hydrogen or methyl and X is a chlorine or bromine atom.

It has been discovered that the compounds of the invention may beobtained by the action of a halogenating agent on the free base or anacid addition salt of a compound of the formula,

where R and R1 have the same significance as given above. Some of thehalogenating agents which may be used to effect this transformation arethlonyl chloride, thionyi bromide, phosphorus oxychloride, phosphorusoxybromide, phosphorus trichloride, phosphorus tribromide, phosphoruspentachloride and the like. The reaction may be carried out by heatingthe two reactants for a short time in the presence or absence of asolvent although in some instances, such as when thionyl chloride orbromide is used, the desired result may also be obtained by merelyallowing the two reactants, in contact with one another, to stand atroom temperature. In general, an excess of the halogenating agent isused and in some cases this excess also serves as a solvent for thereaction.

The compounds of the present invention are powerful sympatholytic agentsand because this ability to block the pressor eilect of epinephrir iethey are especially useful in the treatment of peripheral vasculardiseases and neurogenic hypertension. These compounds also possess anextremely high degree of antihistamine activity and therefore aresuitable in the treatment of allergic conditions due to histamine. Theymay be administered, preferably as the salts or the bases, either orallyor intravenously. The usual intravenous dosage is about 10 to 20 mg.while the oral dosage is about 50 to 100 mg. i

The invention is illustrated by the following examples.

Example 1. p Z-biphenyloxy) ethul-p-chloroethyl-methyl-amineo-omomN-cmcmcl 36.1 g. of the oxalate salt of fi-(2-biphenyloxy)ethyl-,6-hydroxyethyl-methyl-amine is dissolved in water and theresulting solution made alkaline with potassium hydroxide solution. Thefree base is extracted with ether, the ether extract dried and the etherevaporated. The residual free base is heated on a steam bath for onehour with 30 cc. of thionyl chloride, cooled and the solution dilutedwith ether. The hydrochloride salt of the desired product whichseparates from the solution is collected and purified byrecrystallization from either isopropanol or isopropanol-ether mixture;M. P. 168-70 C.

Example 2. ,s Z-biphenyloxu) ethyl-,e-chloroethul-ethul-amine CHiCH:

15 g. of the oxalate salt of fi-(Z-biphenyloxy)ethyl-,8-hydroxyethyl-ethyl-amine is dissolved in water and the solutionmade alkaline with potassium hydroxide solution. The free base isextracted with ether, the ether extracts dried and the ether distilled.The residual free base is treated with 12 cc. of thionyl chloride,heated on a steam bath for fifteen minutes and allowed to standovernight. The mixture is diluted with ether, filtered and thehydrochloride of fi-(Z-biphenyloxy) ethyl-,S-chloroethyl-ethyl aminepurified by recrystallization from isopropanol-ether mixture; M. P.165-6 C.

Example 3. fi (Z-Dtphenyloxy) ethyZ-p-bromoethz/l-ethyl-amine CHiCHl Amixture consisting of 35 g. of fi-(2-biphenyloxy)-ethyl-fi-hydroxyethyl-ethyl-amine and 250 cc. of phosphorus oxybromideis heated at C. with stirring for three hours and then the phosphorusoxybromide distilled oil the reaction mixture under reduced pressure.The residue is added to 750 g. of ice and the resulting mixture altwentyminutes.

cc. with ether, the crystalline hydrochloride of lowed to stand for onehour. 350 cc. of ether is added and the solution made alkaline in thecold with N sodium hydroxide solution. The ether layer is separated andthe aqueous solution extracted with several portions of ether. Thecombined ether extracts are dried for a few minutes over anhydrouspotassium carbonate and the drying agent removed by filtration. Theether filtrate can be evaporated under reduced pressure to obtain thefree base of the desired ,6-(2-biphenyloxy) -ethyl-fl-bromoethylethy1amine or it may be used to prepare the acid addition salts of the freebase. For example, the citrate salt is prepared by treating a portion ofthe ether filtrate with an ether solution containing an equivalentamount of citric acid. The citrate salt which separates is collected andpurified by washing with ether. The hydrohalide salts such as thehydrochloride and hydrobromide salts may be prepared by passing gaseoushydrogen chloride or hydrogen bromide into the ether solution of thefree base. The hydrohalide salt which separates is collected andpurified by recrystallization from isopropanol-ether mixture.

Example 4.p-(2 biphenulory)ethul p-chloroethpl-n-propyl-amine 20.1 g. ofthe oxalate salt of B- (Z-biphenyloxy)ethyl-p-hydroxyethyl-n-propyl-amine is treated with 25 cc. of thionylchloride and the mixture warmed on a steam bath for ten minutes. Thereaction mixture is diluted to 200 cc. with ether,

the solution allowed to stand and the crystalline GO w m g. of ,8 (2biphenyloxy)ethyl-p-hydroxyethyl-isopropyl-amine is added slowly withstirring to 30 cc. of thionyl chloride in an ice bath. .After theaddition has been completed the mixture is allowed to come to roomtemperature and then it is heated on a steam bath for about The mixtureis diluted to 250 fi-(Z biphenyloxy) ethyl p chloroethyl isopropyl-aminecollected and recrystallized from isopropanol-ether mixture; M. P. 13l-3C.

Example 6.p (2-biphenyloru) ethyl-p-chloroethyl-allul-amine 29.7 g. offl-(2-biphenyloxy)ethyl-fi-hydroxyethyl-allyl-amine in 20 cc. of benzeneis added slowly to 30 cc. of thionyl chloride while cooling the mixtureby means of an ice bath. After the addition has been completed themixture is allowed to come to room temperature and then 7 it is heatedon a steam bath for about twenty minutes. The reaction mixture iscooled, diluted to about 500 cc. with dry ether and the crystallinehydrochloride of p (2 biphenyloxy) ethyl-B- chloroethyl-allyl-aminecollected. After recrystallization from isopropanol-ether mixture thesalt melts at-7f C.

Example 7.-p- (Z-biphenylory) ethul-fi-chloroethyl-n-butyl-amine Q0CHzCHaCHaCH:

31.3 g. of fl-(Z-biphenyloxy)ethyl-p-hydroxyethyl-n-butyl-amine is addedslowly to 30 cc. of thionyl chloride while cooling the mixture by meansof an ice bath. The reaction mixture is allowed to come to roomtemperature and then it is heated on a steam bath for fifteen minutes.Addition of about 500 cc. of dry ether to the cool reaction mixturecauses the separation of a viscous oil which crystallizes 0n rubbing.The liquid is decanted and the crude hydrochloride salt offi-(Z-biphenyloxy)ethyl-B-chloroethYl-nbutyl-amine washed with severalfresh portions of dry ether. The crude salt is purified byrecrystallizing it several times from isopropanolether mixture; M. P.117-8 C.

Example 8.-fi- (Z-biphenylozy) e-thyl-p-chloroethyl-isobutuZ-amineb-GHzCHgN-CHgCHzCl 30 g. ofB-(Z-biphenyloxy)ethyl-p-hydroxyethyl-isobutyl-amine is added dropwiseto 25 cc.

of thionyl chloride with stirring while maintaining the temperaturebelow about 10 C. After the addition has been completed the mixture iswarmed on a steam bath for about one-half hour, cooled and diluted toabout 250 cc. with dry ether. The mass which crystallizes on stirring iscollected and washed with ether. The crude El-(2- biphenyloxy)ethyl-fl-chloroethyl-isobutyl-amine hydrochloride is purified byrecrystallization from isopropanol-ether mixture; M. P. -6 0.

' Example '9. fi- (z-biphenuloxy) ethyl-p-bromoethyl-isobutz l-amine CHCHCH:

purified by recrystallization from isopropanol ether mixture.

Example 1 0.- 3-(2-biphen1 loa:y) ethyl-fi-chloroethyl-sec.-butyl-amine10.8 g. of B-(2-biphenyloxy)ethyl-B-hydroxyethyl-sec.-butyl-amine in 10cc. of benzene is added slowly to 15 cc. of thionyl chloride whilecooling the mixture by means of an ice bath. After the addition iscomplete the mixture is warmed for fifteen minutes on a steam bath,cooled and diluted to 250 cc. with dry ether. The crude hydrochloridesalt. of p-(2-biphenyloxy)- ethyl-p-hydroxyethyl-sec.-butyl-amine iscolligated and purified by recrystallization from isopropanol-ethermixture; M. P. 157.5-8 O.

receipts 11.--p-(2-biphenylo:cy)ethyl;p-chlor 'oethyl-n-dmyl-amine 3?omcmcmcnicm -ca,cH.N-cmcmc1 so a; ofp-(2-biphenyloxy)ethyl-p-hydroxyethyl-n-amyl-amine is added slowly to 25cc. of;

thionyl chloride keeping the temperature below 10 C. during theaddition. The mixture is heated on asteam bath for one-hair hour, cooledand diluted to 350 cc. with dry ether. The oily hydrochloride salt ofp-(2-biphenylom) ethylp-chloroethyl-n-amyl-amine which crystallizes onrubbing is collected and recrystallized from isopropanol-ether mixture;M. P. 118-5 C.

mi c 12.B-(2-biphenyloxu)cthyl-p-chloroethyl-n-hexyl-aminc GOcmcmcmcmcmcm o-cmcmN-cnicmci t a le131-p-(2-biphen11l0$il)ethill-fl-chloropropyl-ethyl-amine CHrCHl 29.9 g.of p-(Z-biphenyloxy)ethyl-fi-hydroxypropyl-ethyl-amine is dissolved inabout cc. of benzene and the solution dropped slowly, with stirring,into cc. of thionyl chloride cooled by means of an ice bath. After theaddition has been completed the mixture is warmed on a steam bath forabout one-half hour, cooled and diluted to 250 cc. with dry ether. Theoily hydrochloride which separates irom the solution is crystallizedbyff-rubbing. ether is decanted. the crude salt washed with severalfresh portions of ether and then collected. crystallized fromisopropanol-ether mixture to obtain the pure hydrochloride salt of,8-(2- biphenyloxy) ethyl-p-chloropropyl ethyl amine melting at 158-60"C.

guacamole 14.-pfz-biphenulozy) ethyl-p-bromopropyl-n-propyl-umine Thecrude product can be rethe. phosphorus oxybromide distilled oil underreduced pressure. The-residue is treated with about 750 g. of ice andallowed to stand for about an hour. The solution is covered with etherand made alkaline with 10 N sodium hydroxide in the cold. The etherlayer is separated, the solution extracted with several portions ofether and the combined ether extracts dried for a few minutes overanhydrous potassium carbonate. The drying agent is removed by filtrationand the filtrate containing the free base of the desired product treatedwith an excess of dry, gaseous hydrogen bromide. The precipitatedhydrobromide salt of s (2 biphenyloxylethyl p bromopropyl n propyl-amineis collected and recrystallized from isopropanol-ether mixture.

Other salts such as the oxalate of p-(Z-biphenyloiw)-ethyl-p-bromopropyl n propyl' amine may be prepared byevaporation of the ether from the ether filtrate of the free base and:adding the base to a warm solution of isopropanol containing a molecularequivalent of oxalic acid. Ethyl acetate is added and on cooling theacid oxalate of p-(z -biphenyloxynthyl s bromopropyl-n-propyl-aminecrystallizes out.

Example 15.-.-p- (Z-biphenylomy) ethyl-p-bromopropyl-alZyl-amine 25 g.01' B-(Z-biphenyloxy)ethyl-p-hydroxypropyl-allyl-amine in 25 cc. of drybenzene is added dropwise with stirring to 45 cc. of thionyl bromidewhile maintaining the temperature below about 10 C. After all thehydroxy amine has been added the mixture is warmed on a steam bath forone-half hour, cooled and diluted to 400 cc. with dry ether. Thehydrobromide of fl-(2-biphenyloxy) ethyl p bromopropyl-allylamine whichcrystallizes on rubbing is collected and purified by recrystallizationfrom isopropanel-ether mixture.

In its broader aspects the invention includes the quaternary ammoniumcompounds derived from the p-(2 biphenyloxy) ethyl B haloallrylamineproducts described above. The quaternary ammonium halides may beprepared by treating a free base of the new tertiary fi-haloalkyl aminederivatives with an alkyl or aralkyl halide such as methyl iodide, ethylbromide, benzyl chloride and the like, in an inert organic solvent. Thequaternary ammonium sulfate and sulionates can be prepared in ananalogous man'ner by using reagents such as dimethyl sulfate, methylbenzene suli'onate and methyl toluene sul'fonate instead of the alkyl oraralkyl halides. Some examples of the compounds which can be prepared bythese methods are p-(2-bipheirvloxy)ethyl-pchloroethyl-dimethyl-ammoniumiodide, ,6-(2-biphenyloxy) ethyl p chloroethyl ethyl-methylammoniumbenzene sulfonate, p-(2-biphenyloxy) ethyl pchloroethyl-diethyl-ammonium ptoluene sulfonate, p -(2 biphenyloxy)ethyl p chloroethyl dimethyl ammonium methosuliate andfl-(Z-biphenyloxy) ethyl-p-chloroethyl-ethylbenzyl-ammonium chloride.

The substituted p-(Z-biphenyloxy) ethyl-p-hydroxyalkyl amines used asstarting materials for the preparation of the new halo amines oi thepresent invention may be prepared as described in our copendingapplication, Serial No. 727,286, flled February 7, 1947. According tothe invention described in said copending application substi- 7 tuted (2biphenyloxy) ethyl-p-hydroxyalkyl amines may be produced by reacting ap-(2-biwhere R is a member of the class consisting of lower alkyl andlower alkenyl radicals, R1 is a member of the class consisting ofhydrogen and methyl and X is a member of the class consisting ofchlorine and bromine.

2. A compound of the class consisting of a free base and its acidaddition salts, said free base having the formula,

where R is a lower alkyl radical and R1 is a memberof the classconsisting of hydrogen and methyl.

3. A compound of the class consisting of a free base and its acidaddition salts, said free base having the formula,

where R. is a lower alkenyl radical and R1 is a member of the classconsisting of hydrogen and methyl.

4. The hydrochloride salt of a compound of the formula,

where R is a lower alkyl radical and R1 is a member of the classconsisting of hydrogen and methyl.

5. The hydrochloride salt of a compound of the formula,

where R is a lower alkenyl radical and R1 is a member of the classconsisting of hydrogen and methyl.

6. Process for obtaining an acid addition salt of a compound of theformula,

-C HaCHrlk-CHaZlI-X which comprises reacting a compound of the classconsisting of a free base of the formula,

6-CBICHII!ICHICHOH and acid addition salts thereof, with a halogenatingagent, where R is a member of the class consisting of lower alkyl andlower alkenyl radicals, R1 is a member of the class consisting ofhydrogen and methyl and X is a member of the class consisting ofchlorine and bromine.

GEORGE RIEVESCHL, JR.

ROBERT W. FLEMING.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,187,723 Alquist et a] Jan. 23,1940 2,217,660 Alquist et a1 Oct. 15, 1940 2,252,828 Alquist et al Aug.19, 1941 OTHER REFERENCES Allott, Richter's Organic Chemistry (ElsevierPublishing Co., Inc., 1944) 1, pages 161-162.

1. A COMPOUND OF THE CLASS CONSISTING OF A FREE BASE AND ITS ACIDADDITION SALTS, SAID FREE BASE HAVING THE FORMULA,